U.S. Pat. No. 5,100,889 to Misra et al discloses 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs which are thromboxane A.sub.2 (TXA.sub.2) receptor antagonists or combined thromboxane A.sub.2 receptor antagonist/thromboxane synthetase inhibitors useful, for example, in the treatment of thrombotic and/or vasospastic diseases, and have good duration of action. Examples of compounds disclosed in Misra et al have the structural formula I ##STR3## and including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;
R.sup.1 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl, or amide ##STR4## wherein t is 1 to 12 and R.sub.a is lower alkyl, aryl, cycloalkyl, or cycloalkylalkyl); PA1 R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or R.sup.1 and R.sup.2 together with the nitrogen to which they are linked may form a 5- to 8- membered ring; PA1 R.sup.3 is lower alkyl, aryl or aralkyl; and PA1 R.sup.3a is hydrogen, lower alkyl, aryl or aralkyl.
Misra et al disclose that these compounds may be prepared from the oxazoline XV' ##STR5## which is made to undergo oxidation using manganese dioxide, or nickel peroxide, or preferably cupric bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form the oxazole. ##STR6##
The cupric bromide oxidation is carried out at a temperature of within the range of from about 20.degree. C. to about 70.degree. C., employing a molar ratio of cupric bromide to XV' of within the range of from about 2:1 to about 6:1 and a molar ratio of cupric bromide to DBU of within the range of from about 1:1 to about 1:3 in an inert solvent such as ethyl acetate or preferably ethylacetate/chloroform (1:1, v/v).
The so-formed oxazole may then be hydrolyzed by treatment with an aqueous solution of alkali metal base and then aqueous acid to form the corresponding acid.
In accordance with the present invention, it has now been found that the above oxidation of the oxazoline to the oxazole can be dramatically improved in cost, speed, yield and reproducibility by employing with cupric bromide and DBU, a non-hydride donor amine, preferably hexamethylenetetraamine, in an inert organic solvent such as dichloromethane.